The Multifaceted Mas-Related G Protein-Coupled Receptor Member X2 in Allergic Diseases and Beyond

Abstract

Recent research on mast cell biology has turned its focus on MRGPRX2, a new member of the Mas-related G protein-coupled subfamily of receptors (Mrgprs), originally described in nociceptive neurons of the dorsal root ganglia. MRGPRX2, a member of this group, is present not only in neurons but also in mast cells (MCs), specifically, and potentially in other cells of the immune system, such as basophils and eosinophils. As emerging new functions for this receptor are studied, a variety of both natural and pharmacologic ligands are being uncovered, linked to the ability to induce receptor-mediated MC activation and degranulation. The diversity of these ligands, characterized in their human, mice, or rat homologues, seems to match that of the receptor’s interactions. Natural ligands include host defense peptides, basic molecules, and key neuropeptides such as substance P and vasointestinal peptide (known for their role in the transmission of pain and itch) as well as eosinophil granule-derived proteins. Exogenous ligands include MC secretagogues such as compound 48/80 and mastoparan, a component of bee wasp venom, and several peptidergic drugs, among which are members of the quinolone family, neuromuscular blocking agents, morphine, and vancomycin. These discoveries shed light on its capacity as a multifaceted participant in naturally occurring responses within immunity and neural stimulus perception, as in responses at the center of immune pathology. In host defense, the mice Mrgprb2 has been proven to aid mast cells in the detection of peptidic molecules from bacteria and in the release of peptides with antimicrobial activities and other immune mediators. There are several potential actions described for it in tissue homeostasis and repair. In the realm of pathologic response, there is evidence to suggest that this receptor is also involved in chronic inflammation. Furthermore, MRGPRX2 has been linked to the pathophysiology of non-IgE-mediated immediate hypersensitivity drug reactions. Different studies have shown its possible role in other allergic diseases as well, such as asthma, atopic dermatitis, contact dermatitis, and chronic spontaneous urticaria. In this review, we sought to cover its function in physiologic processes and responses, as well as in allergic and nonallergic immune disease.

MRGPRX2-Mediated Degranulation of Human Skin Mast Cells Requires the Operation of Gαi, Gαq, Ca++ Channels, ERK1/2 and PI3K—Interconnection between Early and Late Signaling

“…With the discovery of Mas-related G protein-coupled receptor member X2 (MRGPRX2) as a key receptor of IgE-independent mast cell (MC) degranulation, two similarly effective routes of degranulation are now established in skin MCs [1,2]. The presumed clinical significance of MRGPRX2 stems from the plethora of ligands, both endogenous and exogenous, that reportedly activate the receptor [1,[3][4][5][6][7][8][9].…”

Mast Cell Activation Syndrome in COVID-19 and Female Reproductive Function: Theoretical Background vs. Accumulating Clinical Evidence

“…In addition to the mentioned FcϵRI and FcγR, MCs express other receptors involved in their activation and/or immune response. Some of the most important receptors include Fc receptors for IgA and IgG; a G protein-coupled receptor known as MRGPRX2; angiotensin-converting enzyme 2 (ACE2) receptor; Toll-like receptors (TLRs) and other receptors for pathogen-associated molecular patterns (PAMPs); receptors for cytokines/chemokines, corticotropin releasing hormone, estrogen and progesterone; and complement receptors (e.g., C3a protein) [125][126][127]. Evidence indicates that the spike protein (S protein) is the main viral structure that SARS-CoV-2 uses to fuse with and enter human host cells by binding to the ACE2 receptor.…”

Mast Cells in the Mammalian Testis and Epididymis—Animal Models and Detection Methods

“…IgE-independent signaling pathways have been related to MC activity in immediate hypersensitivity reactions after the discovery that a diverse range of peptides such as neuropeptide Y or substance P [ 25 ], nerve growth factor (NGF), calcitonin gene-related peptide (CGRP), and pituitary adenylate cyclase-activating peptide and platelet-activating factor (PAF)-4 [ 26 ] can activate human MC through the members of the G protein-coupled receptor family (GPCR), called Mas-related G protein-coupled subfamily of receptors (MRGPRs). Notably, MC membrane receptor MRGPRX2 has been identified as a cause of pseudo-allergic drug reactions [ 26 ].…”